Field of the Invention
The compounds of this invention are derivatives or analogues of a class of naturally occurring chemical compositions known as prostaglandins.
Natural prostaglandins are twenty-carbon atom alicyclic compounds related to prostanoic acid which is represented by the following structural formula: ##SPC1##
By convention, the carbon atoms of I are numbered sequentially from the carboxylic carbon atom. An important stereochemical feature of I is the trans-orientation of the side chains C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20. In I, as elsewhere in this specification, a dotted line (....) indicates projection of the covalent bond below the plane of a reference carbon atom (the alpha-configuration), while a wedged line ( ) represents direction above said plane (the beta-configuration). These notations are applicable to all compounds hereinafter discussed.
The twelve natural prostaglandins which have been isolated to date have the structural formula: ##SPC2##
In which:
L and M may be ethylene or vinylene radicals; and, the five-membered ring ##SPC3##
The natural prostaglandins represented by II, are classified according to the functional groups present in the five-membered ring structure and the presence of double bonds in the ring or chains. Prostaglandins of the F-class (PGF's) are characterized by .alpha.-oriented hydroxyl groups at C.sub.9 and C.sub.11 ; those of the E-type (PGE's) have a carbonyl group at C.sub.9 and an .alpha.-oriented hydroxyl group at C.sub.11 ; compounds of the A-series (PGA's) contain a carbonyl group at C.sub.9 and a double bond at C.sub.10 (.DELTA..sup.10, 11); and members of the B-class (PGB's) have a carbonyl group at C.sub.9 and unsaturated bond between C.sub.8 and C.sub.12 (.DELTA..sup.8, 12). Within each of the F, E, A, and B classes of prostaglandins are three subclassifications based upon the presence of double bonds in the side chains at C.sub.5, C.sub.13, or C.sub.17. The presence of a trans-unsaturated bond only at C.sub.13 is indicated by the subscript numeral 1; thus, for example, PGE.sub.1 denotes a prostaglandin of the E-type (carbonyl at C.sub.9 and an alpha-hydroxyl at C.sub.11) with a trans-double bond at C.sub.13. The presence of both a trans-double bond at C.sub.13 and a cis-unsaturated bond at C.sub.5 is denoted by the subscript numeral 2, for example, PGE.sub.2. Lastly, a trans-double bond at C.sub.13, a cis-double bond at C.sub.5, and a cis-double bond at C.sub.17 is indicated by the subscript numeral 3, for example, PGE.sub.3. The above notations apply to prostaglandins of the A, B and F series as well, however, in the latter the alpha-orientation of the hydroxyl group at C.sub.9 is indicated by the subscript Greek letter .alpha. after the numerical subscript. Thus PGF.sub.3.sub..alpha. represents 9.alpha.,11.alpha.,15.alpha.-trihydroxy-5,17-cis, 13-trans-prostatrienoic acid (utilizing nomenclature based upon prostanoic acid).
It is important to note that in all natural prostaglandins there is an alpha-oriented hydroxyl group at C.sub.15. In the Cahn-Ingold-Prelog system of defining stereochemistry, this C.sub.15 hydroxyl group is in the S-configuration.
11-desoxy derivatives of PGE and PGF molecules do not occur as such in nature, but constitute a class of compounds which possess biological activity related to the parent compounds. Formula II represents 11-desoxy PGE's and PGF's when ##SPC4##
I.U.P.A.C nomenclature of prostaglandins designates the carboxylic side chain as the parent compound: for example, PGF.sub.3.sub..alpha. is 7-{3.alpha., 5.alpha.-dihydroxy-2.beta.-[(3S)-3-hydroxy-trans-1, Cis-5-octenyl]-1.alpha.-cyclopentyl}-cis-5-heptenoic acid.
Recent research has indicated that the prostaglandins are ubiquitous in animal tissues and that prostaglandins, as well as analogues or derivatives thereof, have important biochemical and physiological effects in mammalian endocrine, reproductive, central and peripheral nervous, sensory, gastro-intestinal, hematic, respiratory, cardiovascular, and renal systems.
In mammalian endocrine systems, experimental evidence indicates prostaglandins are involved in the control of hormone synthesis and release in hormone-secreting glands. In rats, for example, PGE.sub.1 and PGE.sub.2 increase release of growth hormone while PGA.sub.1 increases growth hormone synthesis. In sheep, PGE.sub.1 and PGF.sub.1.sub..alpha. inhibit ovarian progesterone secretion. In a variety of mammals, PGF.sub.1.sub..alpha. and PGF.sub.2.sub..alpha. are implicated as luteolytic factors. In mice, PGE.sub.1, PGE.sub.2, PGF.sub.1.sub..alpha. and PGE.sub.1.sub..beta. increase thyroid activity. In hypophysectomized rats, PGE.sub.1, PGE.sub.2 and PGF.sub.1.sub..alpha. stimulate steroidogenesis in the adrenal glands.
In the mammalian male reproductive system, PGE.sub.1 contracts the smooth muscle of the vas deferens. In the female reproductive system, PGE and PGF.sub..alpha. compounds contract uterine smooth muscle. In general, PGE's, PGB's and PGA's relax in vitro human uterine muscle strips, while PGF.sub..alpha.'s contract such isolated preparations. PGE compounds in general promote fertility in the female reproductive system while PGF.sub.2.sub..alpha. has antifertility effects. PGF.sub.2.sub..alpha. also is believed to be involved in the mechanism of menstruation. In general, PGE.sub.2 exerts potent oxytocic effects in inducing labor, while PGF.sub.2.sub..alpha. induces spontaneous abortions in early pregnancy.
PGF.sub..alpha.'s and PGE's have been isolated from a variety of nervous tissue and they have been postulated to serve a neurotransmitter role. PGE.sub.1 retards whereas PGF.sub.2.sub..alpha. facilitates transmission in motor pathways in the CNS. It has been reported that PGE.sub.1 and PGE.sub.2 inhibit transmitter release from adrenergic nerve endings in the guinea pig.
Prostaglandins stimulate contraction of gastrointestinal smooth muscle in vivo and in vitro. In dogs, PGA.sub.1, PGE.sub.1 and PGE.sub.2 inhibit gastric secretion. PGA.sub.1 exhibits similar activity in man.
In most mammalian respiratory tracts, PGE's and PGF.sub..alpha.'s relax in vitro preparation of tracheal smooth muscle. In in vitro preparations, PGE.sub.1 and PGE.sub.2 relax human smooth muscle while PGF.sub.2.sub..alpha. contracts such preparations. PGE and PGF compounds are normally found in the human lung, and it has been postulated that some cases of bronchial asthma involve an imbalance in the production or metabolism of those compounds.
Prostaglandins have been shown to be involved in certain hematic mechanisms in mammals. PGE.sub.1, for example, inhibits thrombogenesis in vitro through its effects on blood platelets.
In a variety of mammalian cardiovascular systems, PGE's and PGA's are vasodilators whereas PGF.sub..alpha.'s are vasoconstrictors, by virtue of their action on vascular smooth muscle.
Prostaglandins are naturally found in the kidney and reverse experimental and clinical renoprival hypertension.
The clinical implications of prostaglandins and derivatives or analogues thereof are far-ranging and include, but are not limited to the following: in obstetrics and gynecology, they may be useful in fertility control, treatment of menstrual disorders, induction of labor, and hormone disorders; in gastroenterology, they may be useful in the treatment of peptic ulcers, and various disorders involving motility, secretion, and absorption in the gastrointestinal tract; in the respiratory area, they may be beneficial in the therapy of bronchial asthma and other diseases involving bronchoconstriction; in hematology, they may have utility as anti-clotting agents in diseases such as venous thrombosis, thrombotic coronary occlusion and other diseases involving thrombi; in circulatory diseases they may have therapeutic utility in hypertension, peripheral vasopathies, and cardiac disorders.
In general, the natural prostaglandins affect smooth muscle regardless of origin in mammalian systems both in vivo and in vitro. This activity allows a rapid bioassay of prostaglandin derivatives or analogues by use of isolated muscle strips in vitro. (Cf. Bergstrom et al., Pharmacol. Rev., 20:1[1968]; Ferreira and Vane, Nature, 216:868 [1961].)
The field to which this invention pertains is discussed in the following references: The Prostaglandins, Vol. I., P. Ramwell, Ed., New York, Plenum Press, 1973; Ann. N.Y. Acad. Sci., 180:1-568 (1971); and Higgins and Braunwald, J. Am. Med. Assn., 53:92-112 (1972).